DESCRIPTION: Myocardial infarction (Ml), the focal loss of cardiac muscle caused by ischemia, is the leading cause of death in this country. One reason why morbidity and mortality are intimately associated with Ml is that the human heart has an extremely limited ability to repair itself through regeneration of cardiomyocytes (CMs), the contractile cells of the heart. By contrast with mammals, the teleost zebrafish displays a highly efficient regenerative response to cardiac injury, able to renew up to 20% of resected ventricular myocardium. How new CMs originate during regeneration is poorly understood. The objective of this proposal is to exploit zebrafish as a model for understanding the cellular and molecular mechanisms of myocardial regeneration. Previous studies have documented how dedifferentiation, a programmed reduction in the specialized, functional components of a mature, differentiated cell, generates precursor cells during regeneration of the limb, tail, or lens in lower vertebrates. It is believed that the origin, proliferation, and patterning of these precursors are controlled by common embryonic signaling pathways. The overall hypothesis of our proposal is that myocardial damage in the zebrafish activates molecular programs that regulate a transition from contractile, non-proliferating cardiac muscle to regenerative CMs that proliferate and are patterned. To test this hypothesis, we propose three specific aims: 1) Define myocardial changes during regeneration This will include detailed studies of ultrastructural differentiation, gene expression, cellular proliferation, and cardiac function. We will also compare injury-induced myocardial gene expression between zebrafish and mice. 2) Determine the functions of Fibroblast growth factor (Fgf) signaling in myocardial regeneration. We will examine how experimental increases or decreases in Fgf signaling activity affect regenerative cardiogenesis, using new inducible transgenic lines that facilitate modulation of signaling through Fg receptors. 3) Identify the functions of retinoic acid (RA) signaling in myocardial regeneration. We wil generate and analyze transgenic lines that facilitate expression of a dominant-negative or constitutive! active RA receptor isotype. Our molecular genetic approach in zebrafish will provide a foundation fo understanding important regulatory mechanisms active during myocardial regeneration, and may lead t approaches for comprehending, and possibly enhancing, the limited regenerative response displayed b humans after Ml.